Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression

Serezani, Carlos H.; Lewis, Casey; Jancar, Sonia; Peters-Golden, Marc
February 2011
Journal of Clinical Investigation;Feb2011, Vol. 121 Issue 2, p671
Academic Journal
journal article
Activation of NF-κB and 5-lipoxygenase-mediated (5-LO-mediated) biosynthesis of the lipid mediator leukotriene B4 (LTB4) are pivotal components of host defense and inflammatory responses. However, the role of LTB4 in mediating innate immune responses elicited by specific TLR ligands and cytokines is unknown. Here we have shown that responses dependent on MyD88 (an adaptor protein that mediates signaling through all of the known TLRs, except TLR3, as well as IL-1β and IL-18) are reduced in mice lacking either 5-LO or the LTB4 receptor BTL1, and that macrophages from these mice are impaired in MyD88-dependent activation of NF-κB. This macrophage defect was associated with lower basal and inducible expression of MyD88 and reflected impaired activation of STAT1 and overexpression of the STAT1 inhibitor SOCS1. Expression of MyD88 and responsiveness to the TLR4 ligand LPS were decreased by Stat1 siRNA silencing in WT macrophages and restored by Socs1 siRNA in 5-LO-deficient macrophages. These results uncover a pivotal role in macrophages for the GPCR BLT1 in regulating activation of NF-κB through Stat1-dependent expression of MyD88.


Related Articles

  • Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. Babitt, Jodie L.; Huang, Franklin W.; Yin Xia; Sidis, Yisrael; Andrews, Nancy C.; Lin, Herbert Y.; Xia, Yin // Journal of Clinical Investigation;Jul2007, Vol. 117 Issue 7, p1933 

    Systemic iron balance is regulated by hepcidin, a peptide hormone secreted by the liver. By decreasing cell surface expression of the iron exporter ferroportin, hepcidin decreases iron absorption from the intestine and iron release from reticuloendothelial stores. Hepcidin excess has been...

  • SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. Evel-Kabler, Kevin; Song, Xiao-Tong; Aldrich, Melissa; Huang, Xue F.; Chen, Si-Yi // Journal of Clinical Investigation;Jan2006, Vol. 116 Issue 1, p90 

    DC-based tumor vaccine research has largely focused on enhancing DC maturation/costimulation and antigen presentation in order to break tolerance against self tumor-associated antigens. DC immunization can activate autoreactive T cells but rarely causes autoimmune pathologies, indicating that...

  • FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice. Kamagate, Adama; Shen Qu; Perdomo, German; Dongming Su; Dae Hyun Kim; Slusher, Sandra; Meseck, Marcia; Dong, H. Henry; Qu, Shen; Su, Dongming; Kim, Dae Hyun // Journal of Clinical Investigation;Jun2008, Vol. 118 Issue 6, p2347 

    Excessive production of triglyceride-rich VLDL is attributable to hypertriglyceridemia. VLDL production is facilitated by microsomal triglyceride transfer protein (MTP) in a rate-limiting step that is regulated by insulin. To characterize the underlying mechanism, we studied hepatic MTP...

  • A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy. Narayanan, Priyadharshini; Lapteva, Natalia; Seethammagari, Mamatha; Levitt, Jonathan M.; Slawin, Kevin M.; Spencer, David M. // Journal of Clinical Investigation;Apr2011, Vol. 121 Issue 4, p1524 

    The in vivo therapeutic efficacy of DC-based cancer vaccines is limited by suboptimal DC maturation protocols. Although delivery of TLR adjuvants systemically boosts DC-based cancer vaccine efficacy, it could also increase toxicity. Here, we have engineered a drug-inducible, composite activation...

  • Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16 Ink4a loss. Debies, Michael T.; Gestl, Shelley A.; Mathers, Jessica L.; Mikse, Oliver R.; Leonard, Travis L.; Moody, Susan E.; Chodosh, Lewis A.; Cardiff, Robert D.; Gunther, Edward J. // Journal of Clinical Investigation;Jan2008, Vol. 118 Issue 1, p51 

    Breast cancers frequently progress or relapse during targeted therapy, but the molecular mechanisms that enable escape remain poorly understood. We elucidated genetic determinants underlying tumor escape in a transgenic mouse model of Wnt pathway-driven breast cancer, wherein targeted therapy is...

  • Phosphorylation substrates and altered signalling in leukemias caused by BCR/ABL. Groffen, J.; De Jong, R.; Haataja, L.; Kaartinen, V.; Heisterkamp, N. // Leukemia (08876924);Apr1999 Supplement 1, Vol. 13, pS81 

    The article presents information related to a study which demonstrates that tyrosine-phosphorylated proteins which specifically bind to the Crkl SH2 domain in the leukemic tissues of P190 BCR/ABL transgenic mice are identical to Hef1 /Cas-L. According to the study, Hef1 /Cas-L is similar to p130...

  • Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. Li, Andrew C.; Binder, Christoph J.; Gutierrez, Alejandra; Brown, Kathleen K.; Plotkin, Christine R.; Pattison, Jennifer W.; Valledor, Annabel F.; Davis, Roger A.; Willson, Timothy M.; Witztum, Joseph L.; Palinski, Wuff; Glass, Christopher K.; Palinski, Wulf // Journal of Clinical Investigation;Dec2004, Vol. 114 Issue 11, p1564 

    PPARalpha, beta/delta, and gamma regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of...

  • Liver X receptors as integrators of metabolic and inflammatory signaling. Zelcer, Noam; Tontonoz, Peter // Journal of Clinical Investigation;Mar2006, Vol. 116 Issue 3, p607 

    The liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. LXRs function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types. Once activated, LXRs...

  • TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice. González-Navajas, José M.; Fine, Sean; Law, Jason; Datta, Sandip K.; Nguyen, Kim P.; Yu, Mandy; Corr, Maripat; Katakura, Kyoko; Eckman, Lars; Lee, Jongdae; Raz, Eyal; González-Navajas, José M // Journal of Clinical Investigation;Feb2010, Vol. 120 Issue 2, p570 

    TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4+ T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics